The suitability for large-scale screening and the transparent nature during embryonic and larval stages make zebrafish an attractive system for small molecule screening in an intact organism, with aims both to identify therapeutic compounds and to understand biological mechanisms. Dopaminergic (DA) neurons play important roles in regulating movement, motivational behaviors, and hormonal homeostasis. Deregulation of the development and/or function of DA neurons have been implicated in neuropsychiatric disorders such as addiction, schizophrenia, attention deficit hyperactivity disorder (ADHD), as well as the neurodegenerative disorder Parkinson's disease. In this proposal, we seek to identify small molecule compounds that can regulate the in vivo commitment and differentiation of naive progenitor cells toward DA neurons, and to understand the mechanisms of action of these compounds. This study shall not only provide a better understanding of the in vivo mechanisms underlying stem cell commitment/differentiation toward the DA neuronal lineage, but may also discover small molecule tools that can be used for developing useful therapeutics to combat dopamine-system related human disorders. PUBLIC HEALTH RELEVANCE: Our research aims to identify small molecule drug-like compounds that can regulate the commitment and differentiation of pluripotent stem cells into dopaminergic (DA) neurons. The importance of DA neurons is underscored by their involvement in multiple human neurological disorders including Parkinson's disease, schizophrenia, addiction, and autism. Our proposed studies are likely to have a long-term impact on understanding in vivo stem cell behavior and moreover to identify therapeutic compounds that can combat DA system-related disorders.